Strokes in sickle cell anemia (SCA), particularly in children living in Africa, are associated with significant morbidity and an increased rate of premature death. In the US, primary prevention of strokes in children with SCA involves screening for elevated transcranial Doppler ultrasound (TCD) velocity coupled with regular blood transfusion therapy for those with elevated velocities. However, regular blood transfusion is not feasible in Africa due to inadequate supply of safe blood and the reluctance of parents to accept blood transfusion therapy for primary stroke prevention. Promising preliminary data from our feasibility trial in Kano, Nigeria (1R21NS080639-NCE, NCT01801423) support the potential use of moderate dose hydroxyurea (HU) therapy of 20 mg/kg/day for primary prevention of stroke in children with SCA. In the feasibility trial, we screened 338 participants; 92% (23 of 25) of the participants with elevated TCD measurements elected to enroll, 66% (15 of 23; of note 2 participants have not reached their 3 month milestone) of the participants who reached their third month on HU therapy dropped their elevated TCD values to below 200 cm/sec in both left and right middle cerebral arteries; and 89% (210 of 235) of the screened participants with non-elevated TCD measurements agreed to be followed for three years for assessment of background rates of morbidity and mortality. Based on the results from the recently completed NHLBI trial, Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea; NCT01425307), demonstrating that children with an elevated TCD measurement can be switched to HU therapy after one year of blood transfusion without an increase in TCD velocities, coupled with our preliminary trial results indicating a decrease in TCD velocities in 2/3rds of the participants over 3 months, we propose a two center randomized clinical trial to test the following hypothesis: There will be a 66% relative risk reduction of primary strokes in children with SCA, and elevated TCD measurements (n=220), randomly allocated to moderate dose vs. low dose HU therapy (10 vs. 20 mg/kg/day) for 3 years. In preparation for this application, both teams from Nigeria and Ghana have received 1 month of patient-oriented research training at Vanderbilt University School of Medicine. The aims are to: 1) determine the efficacy of moderate vs. low dose HU therapy for primary stroke prevention; 2) determine the efficacy of moderate dose HU therapy for decreasing the incidence of all cause-hospitalization for any cause (pain, acute chest syndrome, infection, or other) when compared to low dose HU therapy; and 3) assess long-term safety of HU therapy (6.5 years) in participants from the feasibility trial with an elevated TCD measurement (n=25) when compared to children with an initial normal TCD (n= 210 followed for at least 3 years). After completion of this trial, we will determine whether moderate dose HU therapy can potentially prevent thousands of strokes in children at high risk in Africa, while simultaneously training the next cadre of physician scientiss in Nigeria and Ghana.